Synthesis of (R)- and (S)-α-trifluoromethyl propanoic acids via asymmetric hydrogenation followed by salt resolution

A highly enantioselective synthesis of (R)- and (S)-α-trifluoromethyl (CF3) propanoic acids has been achieved via asymmetric hydrogenation of 2-trifluoromethylacrylic acid using RuBINAP-Cl2 catalyst followed by salt resolution with threoninol. Both enantiomers can be obtained as threoninol salts in good yield and with high enantiomeric excess. Amide coupling conditions that minimize racemization of the chiral acid have also been developed.

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(2R,3R)-1,3-Dihydroxybutan-2-aminium (R)-3,3,3-trifluoro-2-methylpropanoateC8H16F3NO4[α]D25 = −6.6 (c 1.3, MeOH)Absolute configuration: (2R,3R,R)Source of chirality: Asymmetric hydrogenation and resolutionee = 94%

(2S,3S)-1,3-Dihydroxybutan-2-aminium (S)-3,3,3-trifluoro-2-methylpropanoate ((S)-3)C8H16F3NO4[α]D25 = +7.7 (c 0.55, MeOH)Absolute configuration: (2S,3S,S)Source of chirality: Asymmetric hydrogenation and resolutionee = 92%

(R)-3,3,3-Trifluoro-2-methyl-1-(4-phenylpiperi-din-1-yl)propan-1-oneC15H18F3NO[α]D25 = −2.0 (c 0.3, MeOH)Absolute configuration: (R)Source of chirality: Chiral acid starting material (R)-3ee = 88%